{"doi":"10.1152/ajpcell.00083.2020","title":"Regulation of Na/K-ATPase expression by cholesterol: isoform specificity and the molecular mechanism","abstract":"We have reported that the reduction in plasma membrane cholesterol could decrease cellular Na/K-ATPase α1-expression through a Src-dependent pathway. However, it is unclear whether cholesterol could regulate other Na/K-ATPase α-isoforms and the molecular mechanisms of this regulation are not fully understood. Here we used cells expressing different Na/K-ATPase α isoforms and found that membrane cholesterol reduction by U18666A decreased expression of the α1-isoform but not the α2- or α3-isoform. Imaging analyses showed the cellular redistribution of α1 and α3 but not α2. Moreover, U18666A led to redistribution of α1 to late endosomes/lysosomes, while the proteasome inhibitor blocked α1-reduction by U18666A. These results suggest that the regulation of the Na/K-ATPase α-subunit by cholesterol is isoform specific and α1 is unique in this regulation through the endocytosis-proteasome pathway. Mechanistically, loss-of-Src binding mutation of A425P in α1 lost its capacity for regulation by cholesterol. Meanwhile, gain-of-Src binding mutations in α2 partially restored the regulation. Furthermore, through studies in caveolin-1 knockdown cells, as well as subcellular distribution studies in cell lines with different α-isoforms, we found that Na/K-ATPase, Src, and caveolin-1 worked together for the cholesterol regulation. Taken together, these new findings reveal that the putative Src-binding domain and the intact Na/K-ATPase/Src/caveolin-1 complex are indispensable for the isoform-specific regulation of Na/K-ATPase by cholesterol.","journal":"American Journal of Physiology-Cell Physiology","year":2020,"id":78216,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":407065,"name":"Xin Li","orcid":"0000-0002-5985-003X","position":1,"is_corresponding":false},{"id":407066,"name":"Hui Yu","orcid":"0000-0001-5249-0193","position":2,"is_corresponding":false},{"id":407067,"name":"Isabel Larré","orcid":"0000-0003-0768-3556","position":3,"is_corresponding":false},{"id":401532,"name":"Prabhatchandra Dube","orcid":"0000-0003-2163-5788","position":4,"is_corresponding":false},{"id":368433,"name":"David J. Kennedy","orcid":"0000-0001-5265-0142","position":5,"is_corresponding":false},{"id":30816,"name":"W. H. Wilson Tang","orcid":"0000-0002-8335-735X","position":6,"is_corresponding":false},{"id":407068,"name":"Kristen M. Westfall","orcid":"0000-0003-1934-6477","position":7,"is_corresponding":false},{"id":370093,"name":"Sandrine V. Pierre","orcid":null,"position":8,"is_corresponding":false},{"id":408136,"name":"Zijian Xie","orcid":null,"position":9,"is_corresponding":false},{"id":407069,"name":"Yiliang Chen","orcid":"0000-0001-9786-8305","position":10,"is_corresponding":false},{"id":407064,"name":"Jue Zhang","orcid":"0000-0001-8331-2496","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-18T21:49:40.769098Z","pmid":"32997514","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}